Fluid treatment of a polymeric coating on an implantable medical device

ABSTRACT

A method for modifying a polymeric coating on an implantable medical device, such as a stent, is disclosed. The method includes application of a fluid to a wet or dry polymeric coating with and without drugs.

CROSS REFERENCE

This application is a continuation-in-part of application Ser. No.10/603,889, filed on Jun. 25, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to implantable medical devices, one example ofwhich is a stent. More particularly, the invention relates to a methodof coating such implantable medical devices.

2. Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to remodel the vessel wall.The balloon is then deflated to a smaller profile to allow the catheterto be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings, which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis a stent is implanted inthe lumen to maintain the vascular patency.

Stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the opening wall of the passageway. Typically, stentsare capable of being compressed so that they can be inserted throughsmall lumens using catheters and then expanded to a larger diameter oncethey are at the desired location. Mechanical intervention using stentshas reduced the rate of restenosis as compared to balloon angioplasty.Yet, restenosis is still a significant clinical problem with ratesranging from 20-40%. When restenosis does occur in the stented segment,its treatment can be challenging, as clinical options are more limitedas compared to lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention, but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site. Inorder to provide an efficacious concentration to the treated site,systemic administration of such medication often produces adverse oreven toxic side effects for the patient. Local delivery is a preferredmethod of treatment in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Local delivery thus produces fewer side effects andachieves more favorable results.

One proposed method of medicating stents involves using a polymericcarrier coated onto the stent surface. A composition including asolvent, a dissolved polymer, and a dispersed active agent is applied tothe stent by immersing the stent in the composition or by spraying thecomposition onto the stent. The solvent is allowed to evaporate, leavingon the stent surfaces a coating of the polymer and the active agentimpregnated in the polymer.

A potential shortcoming of the foregoing method of medicating stents isthat the active agent release rate may be too high to provide aneffective treatment. This shortcoming may be especially pronounced withcertain active agents. For instance, it has been found that the releaserate of 40-O-(2-hydroxy)ethyl-rapamycin from a standard polymericcoating can be greater than 50% in about 24 hours in certain releasemedia. Thus, there is a need for a coating that reduces active agentrelease rates in order to provide a more effective release-rate profile.

Another shortcoming of the foregoing method of medicating stents is thatthere can be significant manufacturing inconsistencies. For instance,there can be release rate variability among different stents. There aremany ways to change drug release rate. The most frequent usedmethodology is to vary drug-to-polymer ratio. When a slower or fasterrelease is preferred in a certain drug eluting stent application, thereis a need to have a manufacturing method to achieve it without thechange of drug-polymer formulation.

When some polymers dry on a stent surface to form a coating, differentpolymer morphologies may develop for different stent coatings, even ifthe coating process parameters appear to be consistent. The differencesin polymer morphology may cause the active agent release rate to varysignificantly. These inconsistencies may cause clinical complications.Additionally, when stents are stored, the coating can change and exhibit“release rate drift.” In other words, two substantially similar stentsmay exhibit different release rates based predominantly on the time thestents were stored. Yet another source of release rate variability iscaused by the coating, during the coating process, drying at differentrates.

Thus, there is a need for a method that reduces the stent-to-stentrelease rate variability among stents and over time. The rate of drying,or solvent removal, from the coating can affect the distribution of drugwithin the coating. The present invention provides a method and coatingto meet the foregoing as well as other needs.

SUMMARY

The invention provides a method of manufacturing a drug deliveryimplantable medical device, comprising: applying a composition to thedevice to form a wet coating, the composition comprising a polymer, afirst fluid, and optionally an active agent; applying a second fluid tothe wet coating, the second fluid being substantially or completely freefrom any polymers; and removing the first fluid and the second fluid toform a dry coating.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1E illustrates coatings deposited over an implantable medicalsubstrate in accordance with various embodiments of the presentinvention;

FIG. 2 is a graph of the relationship of heat capacity versustemperature for a polymer;

FIG. 3 is graph of the relationship of elasticity versus temperature fora polymer;

FIG. 4 is a graph of the relationship of specific volume versustemperature for a polymer; and

FIGS. 5A and 5B are Fourier Transform Infrared spectrographs that arereferred to in Example 4.

DETAILED DESCRIPTION Coating

A method of manufacturing a drug eluting, delivery or releasing,implantable device, such as a stent, by using a fluid treatment processis disclosed. The method includes applying a fluid to a wet polymericcoating. Alternatively, the method includes applying a fluid to a drypolymeric coating. The coating can include one or more active agentsdispersed within one or more polymers. The active agent can be, forexample, any substance capable of exerting a therapeutic or prophylacticeffect. “Polymer,” “poly,” and “polymeric” are inclusive ofhomopolymers, copolymers, terpolymers etc., including, but not limitedto, random, alternating, block, cross-linked, graft polymers and polymerblends.

Some of embodiments of the polymeric coating are illustrated by FIGS.1A-1E. The Figures have not been drawn to scale, and the thickness ofthe various layers have been over or under emphasized for illustrativepurposes.

Referring to FIG. 1A, a body of a medical substrate 20, such as a stent,is illustrated having a surface 22. A reservoir layer 24 having apolymer and an active agent (e.g., 40-O-(2-hydroxy)ethyl-rapamycin)dispersed in the polymer is deposited on surface 22. Reservoir layer 24can release the active agent when medical substrate 20 is inserted intoa biological lumen.

Referring to FIG. 1B, medical substrate 20 includes cavities ormicro-pores 26 formed in the body for releasably containing an activeagent, as illustrated by dotted region 28. A barrier layer orrate-reducing membrane 30 including a polymer is disposed on surface 22,covering cavities 26. Barrier layer 30 functions to reduce the activeagent release rate.

Referring to FIG. 1C, medical substrate 20 is illustrated havingreservoir layer 24 deposited on surface 22. Barrier layer 30 is formedover at least a selected portion of reservoir layer 24.

Referring to FIG. 1D, reservoir coating 24 is deposited on a primerlayer 32. Barrier layer 30 is formed over at least a portion ofreservoir layer 24. Primer layer 32 serves as an intermediary layer forincreasing the adhesion between reservoir layer 24 and surface 22.Increasing the amount of active agent mixed within the polymer candiminish the adhesiveness of reservoir layer 24 to surface 22.Accordingly, using an active-agent-free polymer as an intermediaryprimer layer 32 allows for a higher active-agent content for reservoirlayer 24.

FIG. 1E illustrates medical substrate 20 having a first reservoir layer24A disposed on a selected portion of surface 22. First reservoir layer24A contains a first active agent, e.g.,40-O-(2-hydroxy)ethyl-rapamycin. A second reservoir layer 24B can alsobe disposed on surface 22. Second reservoir layer 24B contains a secondactive agent, e.g., taxol. First and second reservoir layers 24A and 24Bare covered by first and second barrier layers 30A and 30B,respectively. One of ordinary skill in the art can appreciate thatbarrier layer 30 can be deposited only on selected areas of reservoirlayer 24 so as to provide a variety of selected release parameters. Suchselected patterns may become particularly useful if a combination ofactive agents are used, each of which requires a different releaseparameter.

By way of example, and not limitation, the impregnated reservoir layer24 can have a thickness of about 0.1 microns to about 20 microns, morenarrowly about 0.5 microns to 10 microns. The particular thickness ofreservoir layer 24 is based on the type of procedure for which medicalsubstrate 20 is employed and the amount of the active agent to bedelivered. The amount of the active agent to be included on medicalsubstrate 20 can be further increased by applying a plurality ofreservoir layers 24 on top of one another. Barrier layer 30 can have anysuitable thickness, as the thickness of barrier layer 30 is dependent onparameters such as, but not limited to, the desired rate of release andthe procedure for which the stent will be used. For example, barrierlayer 30 can have a thickness of about 0.1 to about 10 microns, morenarrowly from about 0.25 to about 5 microns. Primer layer 32 can haveany suitable thickness, examples of which can be in the range of about0.1 to about 10 microns, more narrowly about 0.1 to about 2 microns.

Fluid Treatment of the Coating

The implantable medical device manufactured in accordance withembodiments of the present invention may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient. In theinterests of brevity, methods of manufacturing a drug eluting ordelivery stent are described herein. However, one of ordinary skill inthe art will understand that other medical substrates can bemanufactured using the methods of the present invention.

As noted above, the method of the present invention includes applying afluid to a wet or dry polymeric coating. Alternatively, the wet or drypolymeric coating can be formed on the stent surface as described infurther detail herein. The coatings illustrated in FIGS. 1A-1E, forexample, can be exposed to the fluid treatment process.

“Dry coating” is defined as a coating with less than about 10% residualfluid (e.g., solvent(s) and/or water) content (w/w). In one embodiment,the coating has less than about 2% residual fluid content (w/w), andmore narrowly less than about 1% residual fluid content (w/w).

In some embodiments, the fluid can be applied to a wet polymericcoating. “Wet coating” is defined as a coating with more than about 1%fluid (e.g., solvent(s) and/or water) content (w/w). In one embodiment,the coating has more than about 2% residual fluid content (w/w). In someembodiments, more than about 5%, 10%, 20%, 30%, 40%, or 50% residualfluid content (w/w).

The amount of residual fluids in the coating can be determined by GasChromatograph (GC), a Karl Fisher, or ThermoGravimetric Analysis (TGA),study. For example, a coated stent can be extracted with a suitablesolvent that extracts out any residual coating solvent but does notdissolve the coating polymer. This extract is then injected into a GCfor quantification. In another example, a coated stent can be placed inthe TGA instrument, and the weight change can be measured at 100° C. asan indication of water content, or measured at a temperature equal tothe boiling temperature of the solvent used in the coating as anindication of the solvent content.

“Fluid” is defined as a liquid, vapor or a combination of liquids and/orvapors (e.g., mixture of two or more fluids) that is completely orsubstantially free from a polymeric substance. In one embodiment, thefluid comprises one or more active agents or drugs. In anotherembodiment, the fluid is also completely or substantially free from anyactive agents or drugs. “Substantially free” means that there is morefluid than the other substance (i.e., polymer and/or drug and/or otheringredient) (w/w). In one embodiment, the fluid has less than 0.05% ofthe substance (i.e., polymer and/or drug and/or other ingredient) (w/w),more narrowly less than 0.01% (w/w) of the substance. “Completely” meansthat the fluid has 0% (w/w) of such substances.

In some embodiments, the fluid can be chloroform, acetone,cyclohexanone, water, dimethylsulfoxide, propylene glycol methyl ether,iso-propylalcohol, n-propylalcohol, methanol, ethanol, tetrahydrofuran,dimethylformamide, dimethylacetamide, benzene, toluene, xylene, hexane,cyclohexane, pentane, heptane, octane, nonane, decane, decalin, ethylacetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol,diacetone alcohol, benzyl alcohol, 2-butanone, dioxane, methylenechloride, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane,ethylene oxide chlorobenzene, 1,1,1-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, acetonitrile, hexamethylphosphoramide, methyl ethyl ketone, and any mixtures thereof, in anyproportion. In some embodiments, the fluid can specifically exclude anyof the mentioned samples or combination of samples. For example, thefluid can be acetone, but not hexane. As another example, the fluid canbe acetone and formamide but not hexane with any of the other mentionedsamples. In some embodiments, the fluid is a vapor including acycloether such as tetrahydrofuran or ethylene oxide. For someembodiments, vapor can penetrate the dry coating and act as aplasticizer or an annealing agent.

In one embodiment, the coating is subjected to the fluid treatment byapplying the fluid to the coating to modify the active agent releaserate. The fluid acts as a solvent or is a solvent for the active agentin the coating by at least partially dissolving the active agent.“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed mixture atthe molecular- or ionic-size level. When acting as a solvent for theactive agent, in one embodiment, the fluid is capable of dissolving atleast about 5 mg of the active agent in about 1 L of the liquid phase ofthe fluid at ambient pressure and temperature, or at least about 50 mgof the active agent in about 1 L of the liquid phase of the fluid atambient pressure and temperature.

In some embodiments, the fluid should not cause the active agent tocluster together, precipitate, phase separate, crystallize or solidifyin the wet or dry coating, as is understood by those skilled in the art.In some embodiments, the fluid would cause the active agent to cluster,precipitate, phase separate, crystallize and/or solidify in the wet ordry coating.

In some embodiments, particular polymer and fluid combinations can beselected to desirably affect the polymer morphology and/or drugdistribution within the coating in order to modify the active agentrelease rate. For instance, a particular polymer and fluid combinationcan be selected to cause the polymer in the coating to swell asdescribed in Examples 2-4 below. It is also possible to select acombination that advantageously causes the polymer to partially dissolveon the coating. By causing the polymer to partially dissolve on thecoating, the fluid can remove all or a substantial portion of defectsfrom the surface of the coating. A volatile fluid that partiallydissolves the polymer (and in some embodiments, does not dissolve thedrug) can be used to form a thin membrane of the polymer on the surfaceof the coating that is substantially free of the active agent.

If the fluid causes the polymer to partially dissolve and/or swell, thefluid used for the process and the process parameters can be selected toprevent the removal of the polymer from the coating. For example, afluid can be selected that is a more effective solvent for the activeagent than the polymer to prevent the polymer from being removed fromthe coating. Therefore, some of the active agent can be dissolved in thefluid before the polymer is washed away from the coating. In addition, avolatile fluid, e.g., a fluid having a liquid phase with a boilingtemperature below 60° C. at atmospheric pressure, can be selected toprevent the polymer from being removed from the coating. In someembodiments the fluid can be considered non-volatile, with a boilingtemperature above 80° C. at atmospheric pressure, as is understood byone having ordinary skill in the art.

In one embodiment, the fluid contact time is brief. The polymer does nothave time to partially dissolve or even relax. The drug, on the otherhand, due to its relatively low molecular weight, can be extracted tothe surface or out of surface. As a result, the drug release can befaster or slower. Low molecular weight drugs, for example, can be of amolecular weight less than about 2000, less than about 1000, morenarrowly, less than about 500. As a result, the drug release can befaster or slower.

In another embodiment, the fluid is a good solvent to the drug, but notthe polymer. When contacting the fluid with the coating, the polymersurface structure is not affected; however, the drug distribution isdisturbed, which leads to the change of drug release rate. For example,in one embodiment, the second fluid at least partially dissolves in theactive agent, but does not dissolve in the polymer.

The fluid treatment can be beneficial because, without the fluidtreatment, the active agent (e.g., 40-O-(2-hydroxy)ethyl-rapamycin) candiffuse from the polymer matrix at a rate that could be too high or toolow for certain clinical conditions. For example, by using the processof the present invention, a fluid can be applied to the coating for asufficient duration effective to decrease the release rate of40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, byabout 50% as compared to a control group, as demonstrated in Example 3below.

Without being bound by any particular theory, it is believed that thediffusion rate of the active agent from the polymer of the presentinvention can be modified because the fluid treatment modifies thepolymer morphology and/or redistributes the solid state concentration ofthe active agent within the coating. For example, in one embodiment ofthe present invention, the fluid used for the treatment causes thepolymer in the coating to swell, and at the same time, solubilizes theactive agent in the coating. The fluid therefore extracts a portion ofthe active agent from the surface layer of the coating, and causes thepolymer to redistribute at the surface of the coating to form a thinmembrane on the surface that is substantially free of the active agent.The thin membrane of the polymer at the surface can reduce the activeagent release rate from the deeper regions in the final coating.

In another embodiment of the present invention, the coating is subjectedto a fluid treatment by applying a fluid to the coating for a sufficientduration to increase the percent crystallinity of the polymer in thecoating. Methods of determining the percent crystallinity of the polymerare described below.

By increasing the percent crystallinity of the polymer in the coating,the fluid treatment process can address some of the shortcomings ofconventional coating techniques. For instance, the diffusion rate of theactive agent from the polymer of the present invention can be modifiedby selecting a fluid which increases the percent crystallinity of thepolymer in the coating without substantially extracting the drug. Suchfluid can swell the polymer, but rarely solvate the drug.

By bringing the drug-polymer coating to the stable state at time zero orby increasing the percent crystallinity of the polymer in the coating,the fluid treatment process of the present invention can also increasethe manufacturing consistency of drug eluting or delivery stents byreducing the variability of the release rate of active agents amongstents. By exposing a stent coating to a fluid treatment process, forexample, the variance of the mean active agent release rate in a 24 hourperiod can be decreased so that the variance is lower than the varianceof the mean release rate for a baseline group of stents (i.e., stentswhich have not been subjected to a fluid treatment process). Support forthe reduction of the variability of the release rate of active agentsamong stents is illustrated in Table 8 below.

Without being bound by any particular theory, it is believed that thefluid treatment process can increase manufacturing consistency by movinga polymeric stent coating closer to a kinetic or thermodynamicequilibrium. For example, if a semicrystalline polymer is employed inthe coating composition, when volatile solvents are used in the coatingcomposition, the polymer does not have an opportunity to fullycrystallize before the solvent is removed to form the dry coating. Thefluid treatment process can be used to improve polymer morphology byincreasing the percent crystallinity of the polymer. In this case, thesolvent can only swell the polymer but does not solvate the drug. If anamorphous polymer or crystalline polymer is used in a formulation, thefluid treatment can redistribute the drug to a thermodynamicallyfavorable state. In this case, the fluid preferably solvates the drugrather than the polymer.

The fluid treatment process can also reduce the release rate drift overtime by increasing the percent crystallinity of the polymer in thecoating or bringing the coated stents to thermodynamic stable stateearly. “Release rate drift” refers to the phenomenon in which therelease rate of an active agent from a polymeric coating can change overtime, for instance, while the stent is in storage. As mentioned, releaserate drift may occur because of changes in the morphology of a polymericcoating over a period of time. The fluid treatment process can increasethe percent crystallinity of the polymer or redistribute the drug inamorphous or crystalline polymer so that the polymer is in athermodynamically or kinetically stable state, thereby reducing thechanges in the morphology of a polymeric coating over time. The solventtreatment process, therefore, can improve the self-life of the stentproduct.

“Percent crystallinity” refers to the percentage of the polymer materialthat is in a crystalline form. In one embodiment of the presentinvention, the polymer is a semicrystalline polymer having between 10and 75 percent crystallinity. For example, poly(vinylidenefluoride-co-hexafluoroisopropylene) can achieve about 20% crystallinitywhen the vinylidene fluoride to hexafluoroisopropylene ratio is 85:15.Also, by example, poly(vinylidene fluoride) can achieve about a 65percent crystallinity, and poly(6-aminocaproic acid) can achieve about a64 percent crystallinity.

Those of ordinary skill in the art understand that there are severalmethods for determining the percent crystallinity in polymers. Thesemethods are, for example, described in L. H. Sperline, Introduction toPhysical Polymer Science (3rd ed. 2001). The first involves thedetermination of the heat of fusion of the whole sample by calorimetricmethods. The heat of fusion per mole of crystalline material can then beestimated independently by melting point depression experiments. Thepercent crystallinity is then given by heat of fusion of the wholesample divided by the heat of fusion per mole of crystalline materialtimes 100.

A second method involves the determination of the density of thecrystalline portion through X-ray analysis of the crystal structure, anddetermining the theoretical density of a 100% crystalline material. Thedensity of the amorphous material can be determined from anextrapolation of the density from the melt to the temperature ofinterest. Then the percent crystallinity is given by:${\%\quad{Crystallinity}} = {\frac{\rho_{{expt}\quad 1} - \rho_{amorph}}{\rho_{100\%\quad{cryst}} - \rho_{amorph}} \times 100}$

where ρ_(exptl) represents the experimental density, and ρ_(amorph) andρ_(100% cryst) are the densities of the amorphous and crystallineportions, respectively.

A third method stems from the fact that X-ray diffraction depends on thenumber of electrons involved and is thus proportional to the density.Besides Bragg diffraction lines for the crystalline portion, there is anamorphous halo caused by the amorphous portion of the polymer. Theamorphous halo occurs at a slightly smaller angle than the correspondingcrystalline peak, because the atomic spacing is larger. The amorphoushalo is broader than the corresponding crystalline peak, because of themolecular disorder. This third method can be quantified by thecrystallinity index, CI, where ${CI} = {\frac{A_{c}}{A_{a} + A_{c}}.}$

and where A_(c) and A_(a) represent the area under the Bragg diffractionline and corresponding amorphous halo, respectively.

The fluid can be applied by immersing the stent in the fluid. The stentcan be immersed in the fluid, for example, for about half of one secondto about thirteen hours, more narrowly about 1 second to about 10minutes. The stent should be immersed for a sufficient duration toeffect the desired changes in the polymer morphology and/or drugdistribution.

The fluid can also be applied by spraying the fluid onto the stent witha conventional spray apparatus, or applied by other metering devices.For instance, the stent can be sprayed for one to ten spray cycles(i.e., back and forth passes along the length of the stent) using aspray apparatus to deposit about 0.02 ml to about 100 ml, more narrowly0.1 ml to about 10 ml, of the fluid onto the stent. The spray processcan take place in a vacuum chamber at a reduced pressure (e.g., lessthan 300 mm Hg) in order to raise the fluid concentration in the vaporphase. Also, the stent can be sprayed for one to ten spray cycles usinga spray apparatus to deposit about 0.1 mL/hr to about 50 mL/hr throughan atomization spray nozzle with atomization gas pressures ranging fromabout 1 psi to about 30 psi. As above, the stent should be exposed tothe fluid spray process long enough to effect the desired changes in thepolymer morphology.

The fluid can be applied on the glove first and the stents are rolled onthe glove to get wet. The rolling cycle can be one to twenty.

The fluid can be applied to the coating at room temperature, greaterthan room temperature, or at a temperature equal to or greater than theglass transition temperature of the polymer. In some embodiments, thefluid can be chilled below room temperature. The fluid temperature canbe between 25° C. and 0° C. In some embodiments, the fluid temperaturecan be at or below 0° C.

The fluid treatment should not adversely affect the chemical propertiesof the active agent present in the coating. In order to prevent possibledegradation of the active agents or the polymers in the coating, thefluid should not react with the active agent in the coating.Additionally, in some embodiments, the fluid should not cause the activeagent to crystallize within the dry polymeric coating. Crystallizationof the active agent may disadvantageously change the active agentrelease rate from the coating when implanted into a biological lumen. Insome embodiments, the fluid may aggregate the active agent and incertain instance, the active agent may crystallize, both of which couldlead to the change of drug release profile.

Because the fluid does not react with the active agent in the coating,the content of the active agent in the coating should be at least 70% ofthe content of the active agent in the coating before the application ofthe fluid. In a preferred embodiment, it should be at least 80%, morepreferably at least 90%, at least 95%, or at least 98%. Most preferablythe change in active agent content should not be greater than 1%.

After the fluid treatment process, the coating can be allowed to dry tosubstantially remove the solvent and the fluid. For instance, theremoval of the solvent and the fluid can be induced by baking the stentin an oven at a mild temperature (e.g., 50° C.) for a suitable durationof time (e.g., 0.5-2 hours). Also, the fluid can be removed by allowingthe fluid to evaporate from the coating. The fluid can also be removedby causing the fluid to evaporate from the coating.

In one embodiment of the present invention, the fluid treatment treatsselected portions of the drug eluting or delivery stent. By treatingonly portions of the stent coating, the stent coating can have avariable drug release profile, for example along the length of thestent. For instance, the release rate at the end segments of the stentcan be reduced relative to the release rate at the middle segment byapplying the fluid only to the end segments.

The fluid treatment process parameters are selected to limit thepenetration of the fluid into the coating. By limiting the treatmentprocess, a coating can be produced in which shallower regions of thecoating have a different coating morphology than deeper regions. Forexample, a volatile fluid (e.g., acetone), or a limited processduration, can be used so that most of the fluid evaporates beforepenetrating into the deep regions of the coating. One of ordinary skillin the art will understand that the fluids chosen or the duration of thefluid treatment will depend on factors such as the desired diffusionrate of the active agent through the polymer, and the inherentcharacteristics of the polymers and active agents used in the coating.

In another embodiment of the present invention, the fluid used for thetreatment is heated to a temperature greater than room temperature asthe fluid is applied to the polymeric coating. The temperature usedshould be below the temperature that significantly degrades the activeagent disposed in the coating.

In one embodiment, the polymer in the coating is a semicrystallinepolymer (e.g., polyvinyl chloride or an ethylene vinyl alcoholcopolymer), and the fluid is heated to the crystallization temperature(T_(c)) of the polymer as the fluid is applied to the polymeric coating.“Crystallization temperature” refers to the temperature at which asemicrystalline polymer has its highest percent crystallinity. Amorphouspolymers do not exhibit a crystallization temperature. Methods ofdetermining a crystallization temperature are described below. Thecrystallization temperature of ethylene vinyl alcohol copolymer (44 mole% ethylene), for instance, is about 415°K (ethylene vinyl alcoholcopolymer (“EVAL”) is commonly known by the generic name EVOH or by thetrade name EVAL). Other examples of crystallization temperatures include396°K for poly(ethylene terephthalate) as measured by differentialscanning calorimetry (as reported by Parravicini et al., J. Appl. Polym.Sci., 52(7), 875-85 (1994)); and 400°K for poly(p-phenylene sulfide) asmeasured by differential scanning calorimetry (as reported by Ding etal. Macromolecules, 29(13), 4811-12 (1996)).

In another embodiment of the present invention, the fluid applied to thepolymeric coating is heated so that the wet or dry coating is exposed toa temperature equal to or greater than the T_(g) of the polymer in thecoating. In some embodiments, the exposure should be long enough so thatthe polymer temperature reaches a temperature equal to or greater thanthe T_(g). Both amorphous and semicrystalline polymers exhibit glasstransition temperatures. Additionally, if the polymer is asemicrystalline polymer, the dry polymeric coating can be exposed to atemperature equal to or greater than the T_(g) but less than the meltingtemperature (T_(m)) of the polymer in the coating. Amorphous regions ofpolymers do not exhibit a T_(m).

T_(g) is the temperature at which the amorphous domains of a polymerchange from a brittle vitreous state to a plastic state at atmosphericpressure. In other words, the T_(g) corresponds to the temperature wherethe onset of segmental motion in the chains of the polymer occurs. Whenan amorphous or semicrystalline polymer is exposed to an increasingtemperature, the coefficient of expansion and the heat capacity of thepolymer both increase as the temperature is raised, indicating increasedmolecular motion. As the temperature is raised, the actual molecularvolume in the sample remains constant, and so a higher coefficient ofexpansion points to an increase in free volume associated with thesystem and therefore increased motional freedom for the molecules. Theincreasing heat capacity corresponds to an increase in heat dissipationthrough movement.

T_(g) of a given polymer can be dependent on the heating rate and can beinfluenced by the polymer's thermal history. Furthermore, the polymer'schemical structure heavily influences the glass transition by affectingmobility. Generally, flexible main-chain components lower T_(g); bulkyside-groups raise T_(g); increasing the length of flexible side-groupslowers T_(g); and increasing main-chain polarity increases T_(g).Additionally, the presence of crosslinking polymeric components canincrease the observed T_(g) for a given polymer. For instance, FIG. 3illustrates the effect of temperature and crosslinking on the modulus ofelasticity of a polymer, showing that forming cross-links in a polymercan increase T_(g) and shift the elastic response to a higherplateau—one that indicates that the polymer has become more glassy andbrittle. Moreover, molecular weight can significantly influence T_(g),especially at lower molecular weights where the excess of free volumeassociated with chain ends is significant.

The T_(m) of a polymer, on the other hand, is the temperature at whichthe last trace of crystallinity in a polymer disappears as a sample isexposed to increasing heat. The T_(m) of a polymer is also know as thefusion temperature (T_(f)). The T_(m) is always greater than the T_(g)for a given polymer.

Like the T_(g), the melting temperature of a given polymer is influencedby polymer structure. The most influential inter- and intramolecularstructural characteristics include structural regularity, bondflexibility, close-packing ability, and interchain attraction. Ingeneral, high melting points are associated with highly regularstructures, rigid molecules, highly close-packed structures, stronginterchain attraction, or two or more of these factors combined.

Referring to FIG. 2, if the coating polymer is a semicrystallinepolymer, as the polymeric coating is exposed to an increasingtemperature, the polymer exhibits three characteristic thermaltransitions represented by first curve 60, second curve 62 and thirdcurve 64. FIG. 2 illustrates the change in heat capacity (endothermic v.exothermic) of a semicrystalline polymer as the polymer is exposed to anincreasing temperature, as measured by the differential scanningcalorimetry (DSC) method. DSC uses the relationship between heatcapacity and temperature as the basis for determining the thermalproperties of polymers and is further described below.

By way of illustration, when a semicrystalline polymer is exposed to anincreasing temperature, the crystallinity of the polymer begins toincrease as the temperature moves beyond T_(g). At and above the T_(g),the increased molecular motion of the polymer allows the polymer chainsto move around more to adopt a more thermodynamically stablerelationship, and thereby increase the percent crystallinity of thepolymer sample. In FIG. 2, the T_(g) is shown as point T_(g) of firstcurve 60, which is the temperature at which half of the increase in heatcapacity (ΔC_(p)) has occurred. The percent crystallinity then increasesrapidly after point T_(g) and is maximized at the T_(c) of the polymer,which is indicated at the point T_(c) (the apex of second curve 62). Asthe temperature continues to increase, the temperature approaches themelting temperature (T_(m)) of the polymer, and the percentcrystallinity decreases until the temperature reaches the meltingtemperature of the polymer (at point T_(m) of curve 64). As noted above,T_(m) is the temperature where the last trace of crystallinity in thepolymer disappears. The total heats of crystallization, ΔH_(c), and theheats of fusion, ΔH_(f), can be calculated as the areas under curves 62and 64. The heat of crystallization and heat of fusion must be equal,but with opposite signs. It should be understood by those skilled in theart that the sample may have some crystallinity to begin with before thethermogram is performed, in which case the areas under the curves 62 and64 will not be equal.

The T_(g) and/or the T_(m) of the polymer that is to be exposed to thefluid treatment should be determined experimentally in order todetermine which temperatures can be used to treat the wet or drypolymeric coating with the heated fluid. As used herein, “test polymer”means the polymer that is measured to determine the T_(g) and/or theT_(m) of th-e polymer. “Coating polymer” means the polymer that isactually applied as a component of the stent coating.

In order to accurately characterize the thermal properties of thecoating polymer, one should consider the number of factors that caninfluence the T_(g) and T_(m) of a polymer. In particular, the factorsinclude (1) the structure of the polymer (e.g., modification of sidegroups and dissimilar stereoregularity); (2) the molecular weight of thepolymer; (3) the molecular-weight distribution (M_(w)/M_(n)) of thepolymer; (4) the crystallinity of the polymer; (5) the thermal historyof the polymer; (6) additives or fillers that are included in thepolymer; (7) the pressure applied to the polymer as the polymer isheated; (8) residual fluids in the polymer and (9) the rate that thepolymer is heated.

One can account for the foregoing factors by using a test polymer thatis substantially the same as the coating polymer, and testing undersubstantially the same conditions as the conditions used to conduct thefluid treatment of the polymeric coating. The test polymer should havethe same chemical structure as the coating polymer, and should havesubstantially the same molecular weight and molecular-weightdistribution as the coating polymer. For example, if the polymer is ablend of copolymers or homopolymers, the test polymer should havesubstantially the same percentage of components as the coating polymer.At the same time, the test polymer should have substantially the samecrystallinity as the coating polymer. Methods of determiningcystallinity are discussed herein. Additionally, the composition used toform the test polymer should include the same compounds (e.g., additivessuch as therapeutic substances) and liquids (e.g., solvent(s) and water)that are mixed with the coating polymer. Moreover, the test polymershould have the same thermal history as the coating polymer. The testpolymer should be prepared under the same conditions as the coatingpolymer, such as using the same solvent, temperature, humidity andmixing conditions. Finally, the heating rate used for measuring thetransition temperature of the test polymer should be substantiallysimilar to the heating rate used to conduct the fluid treatment of thepolymeric coating.

The T_(g) and T_(m) of the test polymer can be measured experimentallyby testing a bulk sample of the polymer. As understood by one ofordinary skill in the art, a bulk sample of the polymer can be preparedby standard techniques, for example those that are outlined in thedocumentation accompanying the instruments used to measure thetransition temperature of the polymer.

There are several methods that can be used to measure the T_(g) andT_(m) of a polymer. The T_(g) and T_(m) can be observed experimentallyby measuring any one of several basic thermodynamic, physical,mechanical, or electrical properties as a function of temperature.Methods of measuring glass transition temperatures and meltingtemperatures are understood by one of ordinary skill in the art and arediscussed by, for example, L. H. Sperling, Introduction to PhysicalPolymer Science, Wiley-Interscience, New York (3rd ed. 2001), and R. F.Boyer, in Encyclopedia of Polymer Science and Technology, Suppl. Vol. 2,N. M. Bikales, ed., Interscience, New York (1977).

The T_(g) of a bulk sample can be observed by measuring the expansion ofthe polymer as the polymer is exposed to increasing temperature. Thisprocess is known as dilatometry. There are two ways of characterizingpolymers through dilatometry. One way is to measure the linearexpansivity of the polymer sample. Another method involves performingvolume-temperature measurements, where the polymer is confined by aliquid and the change in volume is recorded as the temperature israised. The usual confining liquid is mercury, since it does not swellorganic polymers and has no transition of its own through most of thetemperature range of interest. The results may be plotted as specificvolume versus temperature as shown in FIG. 4, which illustrates arepresentative example of a dilatometric study of branched poly(vinylacetate). Since the elbow in volume-temperature studies is not sharp(measurements of T_(g) using dilatometric studies show a dispersion ofabout 20-30° C.), the two straight lines below and above the transitionare extrapolated until they meet. The extrapolated meeting point istaken as the T_(g). A representative example of an apparatus that can beused to measure a T_(g) through dilatometric studies is the DilatometerDIL 402 PC (available from Netzsch, Inc., Exton, Pa.).

Thermal methods can also be used to measure the T_(g) of a bulk sample.Two closely related methods are differential thermal analysis (DTA) anddifferential scanning calorimetry (DSC). Both methods yield peaksrelating to endothermic and exothermic transitions and show changes inheat capacity. A representative example of a DTA apparatus is theRheometrics STA 1500 which provides simultaneous thermal analysisthrough DTA and DSC.

In addition to the information that can be produced by a DTA, the DSCmethod also yields quantitative information relating to the enthalpicchanges in the polymer (the heat of fusion of the temperature, ΔH_(f)).The DSC method uses a servo system to supply energy at a varying rate tothe sample and the reference, so that the temperatures of the two stayequal. The DSC output plots energy supplied against average temperature.By this method, the areas under the peaks can be directly related to theenthalpic changes quantitatively.

Referring to FIG. 2, the T_(g) can be taken as the temperature at whichone-half of the increase in the heat capacity, ΔC_(p), has occurred. Theincrease in ΔC_(p) is associated with the increased molecular motion ofthe polymer.

A method of separating a transient phenomenon such as a hysteresis peakfrom the reproducible result of the change in heat capacity is obtainedthrough the use of modulated DSC. Here, a sine wave is imposed on thetemperature ramp. A real-time computer analysis allows a plot of notonly the whole data but also its transient and reproducible components.Representative examples of modulated DSC apparatuses are those in the QSeries™ DSC product line from TA Instruments, New Castle, Del.

Another representative example of an apparatus that uses DSC as the basetechnology for measuring the T_(g) is a micro thermal analyzer, such asthe μTA™ 2990 product from TA Instruments. A micro thermal analyzer canhave an atomic force microscope (AFM) that is used in conjunction with athermal analyzer. The instrument can be used to analyze individualsample domains identified from the AFM images. In a micro thermalanalyzer such as the μTA™ 2990, the AFM measurement head can contain anultra-miniature probe that functions as a programmable heat source andtemperature sensor. A micro thermal analyzer, therefore, can provideinformation similar to that from traditional thermal analysis, but on amicroscopic scale. For example, the μTA™ 2990 can provide images of asample in terms of its topography, relative thermal conductivity andrelative thermal diffusivity. The μTA™ 2990 can also provide spatialresolution of about 1 μm with a thermal probe and atomic resolution withregular AFM probes. Other advantages of the μTA™ 2990 is that it canheat the polymer sample from ambient to about 500° C. at heating ratesup to 1500° C./minute which allows for rapid thermal characterization(e.g., in less than 60 seconds), and it can hold the sampleisothermically over a broad range of temperatures (e.g., −70 to 300°C.), which allows for thermal characterization over a broad temperaturerange.

Since the notion of the glass-rubber transition stems from a softeningbehavior, mechanical methods can provide direct determination of theT_(g) for a bulk sample. Two fundamental types of measurement prevail:the static or quasi-static methods, and the dynamic methods. Foramorphous polymers and many types of semicrystalline polymers in whichthe crystallinity does not approach 100%, stress relaxation, Gehman,and/or Glash-Berg instrumentation provide, through static measurementmethods, rapid and inexpensive scans of the temperature behavior of newpolymers before going on to more complex methods. Additionally, thereare instruments that can be employed to measure dynamic mechanicalspectroscopy (DMS) or dynamic mechanical analysis (DMA) behavior. Arepresentative example of an apparatus for a DMA method is the DMA 242,available from Netzsch, Inc., Exton, Pa.

Another method for studying the mechanical spectra of all types ofpolymers, especially those that are not self-supporting, is torsionalbraid analysis (TBA). In this case the polymer is dipped onto a glassbraid, which supports the sample. The braid is set into a torsionalmotion. The sinusoidal decay of the twisting action is recorded as afunction of time as the temperature is changed. Because the braid actsas a support medium, the absolute magnitudes of the transitions are notobtained; only their temperatures and relative intensities are recorded.

The T_(g) of a bulk sample of a polymer can also be observed usingelectromagnetic methods. Representative examples of electromagneticmethods for the characterization of transitions in polymers aredielectric loss (e.g., using the DEA 2970 dielectric analyzer, availablefrom TA Instruments, New Castle, Del.) and broad-line nuclear magneticresonance (NMR).

If the thickness of the coating polymer is ultra thin (i.e., less than 1micron), it may be useful to utilize specialized measuring techniques,at least to compare the results with the values determined by measuringa bulk polymer sample to ensure that the bulk values are not affected bythe thickness of the polymer layer. Specialized techniques may be usefulbecause it has recently been observed that the T_(g) of a polymer can beinfluenced by the thickness of the polymer layer. Researchers, forexample, have observed that polystyrene films on hydrogen-passivated Sihad glass transition temperatures that were lower than the bulk value ifthe thickness of the films was less than 0.04 microns. See Forest etal., Effect of Free Surfaces on the T_(g) of Thin Polymer Films,Physical Review Letters 77(10), 2002-05 (September 1996).

Brillouin light scattering (BLS) can be used to measure the T_(g) of apolymer in an ultra thin film. The ultra thin films can be prepared byspin casting the polymer onto a substrate (e.g., the same substrate usedto support the coating polymer on the stent). A spinning apparatus isavailable, for example, from Headway Research, Inc., Garland, Tex. BLScan also be used to find the T_(g) of a polymer in a bulk sample. In BLSstudies of bulk polymers, one measures the velocity ν_(L) of the bulklongitudinal phonon, where ν_(L)=(C₁₁/ρ)^(1/2), C₁₁ is the longitudinalelastic constant, and ρ is the density. Since C₁₁ is a strong functionof ρ, as the sample temperature is changed, the temperature dependenceof ν_(L) exhibits an abrupt change in slope at the temperature at whichthe thermal expansivity is discontinuous, i.e., the T_(g). For thinfilms, BLS probes the elastic properties through observation offilm-guided acoustic phonons. The guided acoustic modes are referred toas Lamb modes for freely standing films. For further discussion of theapplication of BLS for measuring T_(g), see Forest et al., Effect ofFree Surfaces on the Glass Transition Temperature of Thin Polymer Films,Physical Review Letters 77(10), 2002-05 (September 1996) and Forest etal. Mater. Res. Soc. Symp. Proc. 407, 131 (1996).

The T_(g) of an ultra thin polymer film can also be determined by usingthree complementary techniques: local thermal analysis, ellipsometry andX-ray reflectivity. See, e.g., Fryer et al., Dependence of the GlassTransition Temperature of Polymer Films on Interfacial Energy andThickness, Macromolecules 34, 5627-34 (2001). Using ellipsometry (e.g.,with a Rudolph Auto EL nulling ellipsometer) and X-ray reflectivity(e.g., with a Scintag XDS 2000), the T_(g) is determined by measuringchanges in the thermal expansion of the film. Using local thermalanalysis, on the other hand, the T_(g) is determined by measuringchanges in the heat capacity and thermal conductivity of the film andthe area of contact between a probe and the polymer surface.

Table 1 lists the T_(g) for some of the polymers used in the embodimentsof the present invention. The cited temperature is the temperature asreported in the noted reference and is provided by way of illustrationonly and is not meant to be limiting. TABLE 1 METHOD USED TO CALCULATEPOLYMER T_(g) (°K) T_(g) REFERENCE EVAL 330 DMA Tokoh et al., Chem.Express, 2(9), 575-78 (1987) Poly(n-butyl 293 Dilatometry Rogers et al.,J. Phys. methacrylate) Chem., 61, 985-90 (1957) Poly(ethylene-co- 263DSC and DMA Scott et al., J. Polym. (vinyl acetate) Sci., Part A, Polym.Chem., 32(3), 539-55 (1994) Poly(ethylene 343.69 DSC Sun et al., J.Polym. Sci., terephthalate) Part A, Polym. Chem., 34(9), 1783-92 (1996)Poly(vinylidene 243 Dielectric Barid et al., J. Mater. Sci., fluoride)relaxation 10(7), 1248-51 (1975) Poly(p-phenylene 361 DSC Ding, et al.,sulfide) Macromolecules, 29(13), 4811-12 (1996) Poly(6- 325 DSC Gee etal., Polymer, 11, aminocaproic 192-97 (1970) acid) Poly(methyl 367 DSCFernandez-Martin, et al., methacrylate) J. Polym. Sci., Polym. Phys.Ed., 19(9), 1353-63 (1981) Poly(vinyl 363 Dilatometry Fujii et al., J.Polym. Sci., alcohol) Part A, 2, 2327-47 (1964) Poly(epsilon- 208 DSCLoefgren et al., caprolactone) Macromolecules, 27(20), 5556-62 (1994)

By using the methods of measurement described above, one may observemore than one T_(g) for some of these types of polymers. For example,some polymer blends that exhibit two phase systems can have more thanone T_(g) . Additionally, some semicrystalline polymers can have twoglass transitions, especially when they have a higher percentcrystallinity. See Edith A. Turi, Thermal Characterization of PolymericMaterials, Academic Press, Orlando, Fla. (1981). Bulk-crystallizedpolyethylene and polypropylene, for example, can have two glasstransition temperatures at a relatively high percent crystallinity. Thelower of the two transitions is represented as T_(g)(L), which can bethe same as the conventional T_(g) at zero crystallinity. The highertransition is designated as T_(g)(U) and becomes more detectable as thecrystallinity increases. The difference, ΔT_(g)=T_(g)(U)−T_(g)(L), tendsto approach zero as the fractional crystallinity χ approaches zero.

It has also been reported that block and graft copolymers can have twoseparate glass transition temperatures. For some of these polymers, eachT_(g) can be close to the T_(g) of the parent homopolymer. The followingTable 2 lists the glass transition temperatures for representativeexamples of block and graft copolymers. As illustrated by Table 2, mostof these block and graft copolymers exhibit two glass transitiontemperatures. The cited temperatures were reported in Black andWorsfold, J. Appl. Polym. Sci., 18, 2307 (1974) who used a thermalexpansion technique to measure the temperatures. TABLE 2 Lower UpperTotal T_(g) T_(g) M₁ M₂ % M₁ MW (°K) (°K) α-Methylstyrene Vinyl acetate18 103,000 308 455 α-Methylstyrene Vinyl chloride 67 39,000 265 455α-Methylstyrene Styrene 45 61,000 400 — Styrene Methyl 40 70,000 — 371methacrylate Styrene Butyl acrylate 46 104,000 218 372 Styrene Ethyleneoxide 50 40,000 201 373 Styrene Isoprene 50 1,000,000 198 374 StyreneIsobutylene 40 141,000 204 375 Methyl Ethyl acrylate 56 162,000 250 388Methacrylate Methyl Vinyl acetate 50 96,000 311 371 Methacrylate MethylEthyl 50 104,000 342 379 Methacrylate methacrylate

In one embodiment of the present invention, if the polymer exhibits morethan one T_(g), the fluid is heated to exposed the polymer to atemperature equal to or greater than the lowest observed T_(g). It isbelieved that by exposing a polymer to a temperature equal to or greaterthan the lowest T_(g), the release rate of the agent should be reducedby a measurable extent because at least some of the amorphous polymerdomains will be modified during the process. In another embodiment, ifthe polymer exhibits more than one T_(g), the fluid is heated to exposethe polymer to 10 a temperature equal to or greater than the highestobserved T_(g). By exposing the polymer to the highest T_(g), it isbelieved that one can maximize the release rate reduction. Again, withsome embodiments, the duration of exposure is long enough so that thetemperature of the polymer reaches the temperature of the applied fluid.

As noted above, in one embodiment, the polymeric coating can be exposedto a temperature equal to or greater than the T_(g) and lower than theT_(m) of the polymer. There are several types of methods that can beused to measure the T_(m) of a polymer. For example, the meltingtemperature can be observed by measuring visual, physical, and thermalproperties as a function of temperature.

T_(m) can be measured by visual observation by using microscopictechniques. For instance, the disappearance of crystallinity in asemicrystalline or crystalline polymer can be observed with amicroscope, with the sample housed between crossed nicols, or polarizers(i.e., an optical material that functions as a prism, separating lightrays that pass through it into two portions, one of which is reflectedaway and the other transmitted). As a polymer sample is heated, thesharp X-ray diffraction pattern characteristic of crystalline materialgives way to amorphous halos at the T_(m).

Another way of observing the T_(m) is to observe the changes in specificvolume with temperature. Since melting constitutes a first-order phasechange, a discontinuity in the volume is expected. The T_(m) should givea discontinuity in the volume, with a concomitant sharp melting point.Because of the very small size of the crystallites in bulk crystallizedpolymers, however, most polymers melt over a range of several degrees.The T_(m) is the temperature at which the last trace of crystallinitydisappears. This is the temperature at which the largest and/or most“perfect” crystals are melting.

Alternatively, the T_(m) can be determined by using thermomechanicalanalysis (TMA) that uses a thermal probe (e.g., available from PerkinElmer, Norwalk, Conn.). The T_(m) can also be determined with athermal-based method. For example, a differential scanning calorimetry(DSC) study can be used to determine the T_(m). The same process for DSCas described above for the determination of T_(g) can be used todetermine the T_(m). Referring to FIG. 2, the T_(m) of therepresentative polymer is the peak of curve 64.

Table 3 lists the melting temperatures for some of the polymers used inthe embodiments of the present invention. TABLE 3 METHOD USED TO POLYMERT_(m) (°K) CALCULATE T_(m) REFERENCE EVAL 437.3 DMA Tokoh et al., Chem.Express, 2(9), 575-78 (1987) Poly(ethylene 526.38 DSC Sun et al., J.Polym. terephthalate) Sci., Part A, Polym. Chem., 34(9), 1783-92 (1996)Poly(vinylidene 444 Dielectric Barid et al., J. Mater. fluoride)relaxation Sci., 10(7), 1248-51 (1975) Poly(p-phenylene 560 DSC Ding, etal., sulfide) Macromolecules, 29(13), 4811-12 (1996) Poly(6- 498 DSC Geeet al., Polymer, aminocaproic 11, 192-97 (1970) acid) Poly(vinyl 513 TMAFujii et al., J. Polym. alcohol) Sci., Part A, 2, 2327-47 (1964)Poly(epsilon- 330.5 DSC Loefgren et al., caprolactone) Macromolecules,27(20), 5556-62 (1994)

In the embodiments of the present invention, the fluid (e.g., vapor)treatment process can be used to reduced the release rate of an activeagent from polymeric coatings having various coating structures.Referring to FIG. 1A, for instance, reservoir layer 24 has a polymer andan active agent. The polymer in reservoir layer 24 can be exposed to afluid sufficient to reduce the active agent release rate from reservoirlayer 24.

The fluid treatment process can also be directed to a coating having abarrier layer as illustrated in FIGS. 1B-1E. Referring to FIG. 1B, forinstance, an active agent can be deposited in cavities 26, and coveredby barrier layer 30. In one embodiment of the present invention, thepolymer in barrier layer 30 is subjected to the fluid treatment process.

Forming an Active Agent-Containing Coating

The composition containing the active agent can be prepared by firstforming a polymer solution by adding a predetermined amount of a polymerto a predetermined amount of a compatible solvent. The polymer can beadded to the solvent at ambient pressure and under anhydrous atmosphere.If necessary, gentle heating and stirring or mixing can be employed todissolve the polymer in the solvent, for example 12 hours in a waterbath at about 60° C.

Sufficient amounts of the active agent can then be dispersed in theblended polymer-solvent composition. The active agent should be in truesolution or saturated in the blended composition. If the active agent isnot completely soluble in the composition, operations including mixing,stirring, and/or agitation can be employed to homogenize the residues.The active agent can also be first added to a compatible solvent beforemixing with the composition.

The polymer can comprise from about 0.1% to about 35%, more narrowlyfrom about 0.5% to about 20% by weight of the total weight of thecomposition, the solvent can comprise from about 59.9% to about 99.8%,more narrowly from about 79% to about 99% by weight of the total weightof the composition, and the active agent can comprise from about 0.1% toabout 40%, more narrowly from about 0.4% to about 9% by weight of thetotal weight of the composition. Selection of a specific weight ratio ofthe polymer and solvent depends on factors such as, but not limited to,the polymer molecular weight, the material from which the device ismade, the geometrical structure of the device, and the type and amountof the active agent employed.

Representative examples of polymers that can be combined with the activeagent for the reservoir layer include ethylene vinyl alcohol copolymer(commonly known by the generic name EVOH or by the trade name EVAL);polybutylmethacrylate; poly(ethylene-co-vinyl acetate); poly(vinylidenefluoride-co-hexafluoropropene); poly(hydroxyvalerate); poly(L-lacticacid); poly(epsilon-caprolactone); poly(lactide-co-glycolide);poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone;polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lacticacid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester;polyphosphoester urethane; poly(amino acids); cyanoacrylates;poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters)(e.g. PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules,such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid; polyurethanes; silicones; polyesters; polyolefins; polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers;vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halidesand copolymers, such as polyvinylidene fluoride, polyvinylidenefluoride-co-hexafluoropropylene and polyvinylidene chloride;polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such aspolystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers ofvinyl monomers with each other and olefins, such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,styrene-isobutylene-styrene copolymer and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; polyurethanes; rayon; rayon-triacetate; cellulose acetate;cellulose butyrate; cellulose acetate butyrate; cellophane; cellulosenitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

EVAL is functionally a suitable choice of polymer. EVAL may be producedusing ethylene and vinyl acetate monomers and then hydrolyzing theresulting polymer, forming residues of both ethylene and vinyl alcoholmonomers. One of ordinary skill in the art understands that ethylenevinyl alcohol copolymer may also be a terpolymer so as to include smallamounts of additional monomers, for example less than about five (5)mole percent of styrenes, propylene, or other suitable monomers.Ethylene vinyl alcohol copolymers are available commercially fromcompanies such as Aldrich Chemical Company, Milwaukee, Wis., or EVALCompany of America, Lisle, Ill., or can be prepared by conventionalpolymerization procedures that are well known to one of ordinary skillin the art.

Poly(butylmethacrylate) (“PBMA”) and ethylene-vinyl acetate copolymerscan also be especially suitable polymers for the reservoir layer. In oneembodiment, the polymer in the reservoir coating is a mixture of PBMAand an ethylene-vinyl acetate copolymer.

KRATON G-1650 is also a suitable polymer. KRATON is manufactured byShell Chemicals Co. of Houston, Tex., and is a three block copolymerwith hard polystyrene end blocks and a thermoplastic elastomericpoly(ethylene-butylene) soft middle block. KRATON G-1650 contains about30 mass % of polystyrene blocks.

Solef is another suitable polymer. Solef is manufactured by Solvay andit is a random copolymer containing vinylidene fluoride andhexafluoropropylene monomers. Solef 21508 contains about 85% mass ofvinylidene fluoride and 15% of hexafluoropropylene.

Representative examples of solvents that can be combined with thepolymer and active agent include chloroform, acetone, water (bufferedsaline), dimethylsulfoxide, propylene glycol methyl ether,iso-propylalcohol, n-propylalcohol, methanol, ethanol, tetrahydrofuran,dimethylformamide, dimethylacetamide, benzene, toluene, xylene, hexane,cyclohexane, pentane, heptane, octane, nonane, decane, decalin, ethylacetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol,diacetone alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane,methylene chloride, carbon tetrachloride, tetrachloroethylene,tetrachloroethane, chlorobenzene, 1,1,1-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethylphosphoramide, or combinations of these.

The active agent may be any substance capable of exerting a therapeuticor prophylactic effect in the practice of the present invention.Examples of such active agents include antiproliferative,antineoplastic, antiinflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, and antioxidantsubstances as well as combinations thereof. An example of anantiproliferative substance is actinomycin D, or derivatives and analogsthereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue,Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycin I₁,actinomycin X₁, and actinomycin C₁. Examples of antineoplastics includepaclitaxel and docetaxel. Examples of antiplatelets, anticoagulants,antifibrins, and antithrombins include aspirin, sodium heparin, lowmolecular weight heparin, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogs, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist, recombinanthirudin, thrombin inhibitor (available from Biogen), and 7E-3B® (anantiplatelet drug from Centocor). Examples of antimitotic agents includemethotrexate, azathioprine, vincristine, vinblastine, fluorouracil,adriamycin, and mutamycin. Examples of cytostatic or antiproliferativeagents include angiopeptin (a somatostatin analog from Ibsen),angiotensin converting enzyme inhibitors such as CAPTOPRIL (availablefrom Squibb), CILAZAPRIL (available from Hoffman-LaRoche), or LISINOPRIL(available from Merck & Co., Whitehouse Station, N.J.), calcium channelblockers (such as Nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, histamine antagonist, LOVASTATIN (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug from Merck & Co.),monoclonal antibodies (such as PDGF receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitor (available formGlazo), Seramin (a PDGF antagonist), serotonin blockers, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide.Other therapeutic substances or agents that may be appropriate includealpha-interferon, genetically engineered epithelial cells,dexamethasone, estradiol, clobetasol propionate, cisplatin, insulinsensitizers, receptor tyrosine kinase inhibitors and carboplatin.Exposure of the composition to the active agent should not adverselyalter the active agent's composition or characteristic. Accordingly, theparticular active agent is selected for compatibility with the blendedcomposition.

In one embodiment, the drug is rapamycin and functional derivatives orfunctional analogs thereof, such as. In yet another embodiment, the drugis 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name ofEVEROLIMUS). Analogs or derivatives of 40-O-(2-hydroxy)ethyl-rapamycincan also be used, examples of which include, but are not limited to,40-O-(3-hydroxy)propyl-rapamycin and40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycin, and40-O-tetrazole-rapamycin, and ABT-578 by Abbott laboratories.

40-O-(2-hydroxy)ethyl-rapamycin binds to the cytosolic immunophyllinFKBP12 and inhibits growth factor-driven cell proliferation, includingthat of T-cells and vascular smooth muscle cells. The actions of40-O-(2-hydroxy)ethyl-rapamycin occur late in the cell cycle (i.e., lateG1 stage) compared to other immunosuppressive agents such as tacrolimusor cyclosporine which block transcriptional activation of earlyT-cell-specific genes. Since 40-O-(2-hydroxy)ethyl-rapamycin can act asa potent anti-proliferative agent, it is believed that40-O-(2-hydroxy)ethyl-rapamycin can be an effective agent to treatrestenosis by being delivered to a local treatment site from a polymericcoated implantable device such as a stent.

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin can beadvantageously controlled by various methods and coatings as describedherein. In particular, by using the methods and coatings of the presentinvention, the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin, oranalog or derivative thereof, can be less than about 50% in 24 hours.

The 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, inthe reservoir layer can be in the amount of about 50 μg to about 500 μg,more narrowly about 90 μg to about 350 μg, and the polymer can be in theamount of about 50 μg to about 1000 μg, more narrowly about 90 μg toabout 500 μg. When the 40-O-(2-hydroxy)ethyl-rapamycin is blended with apolymer for the reservoir layer, the ratio of40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, topolymer by weight in the reservoir layer can be about 1:2.8 to about1.5:1.

The dosage or concentration of the active agent required to produce atherapeutic effect should be less than the level at which the activeagent produces unwanted toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the active agent required to inhibit the desired cellular activity ofthe vascular region, for example, can depend upon factors such as theparticular circumstances of the patient; the nature of the trauma; thenature of the therapy desired; the time over which the administeredingredient resides at the vascular site; and if other bioactivesubstances are employed, the nature and type of the substance orcombination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal models and using immunohistochemical, fluorescent or electronmicroscopy methods to detect the agent and its effects, or by conductingsuitable in vitro studies. Standard pharmacological test procedures todetermine dosages are understood by one of ordinary skill in the art.

Forming a Barrier Layer

In some coatings, the active agent release rate may be too high to beclinically useful. A barrier layer can reduce this release rate or delaythe time of the starting of the release of the active agent from thereservoir layer.

In accordance with one embodiment, the barrier layer can be applied on aselected region of the reservoir layer to form a rate reducing membrane.The barrier layer can be applied to the reservoir layer before or afterthe fluid treatment. In some embodiments, fluid treatment can be appliedto both the reservoir layer and the barrier layer. If the barrier layeris applied to the reservoir layer before fluid treatment, the solvent inthe barrier layer can be allowed to evaporate to form a dry coatingbefore applying the fluid. Alternatively, the solvent is not allowed toevaporate and the fluid is applied to a wet barrier coating. Similarly,if the barrier layer is applied to the reservoir layer after fluidtreatment, the barrier layer should be applied after the fluid has beenallowed to evaporate from the coating. In some embodiments, the barrierlayer can be applied before all of the fluid has been removed.

The composition for the barrier layer can be substantially free ofactive agents. Alternatively, for maximum blood compatibility, compoundssuch as polyethylene glycol, heparin, heparin derivatives havinghydrophobic counter ions, or polyethylene oxide can be added to thebarrier layer, or disposed on top of the barrier layer.

The choice of polymer for the barrier layer can be the same as theselected polymer for the reservoir. The use of the same polymer, asdescribed for some of the embodiments, significantly reduces oreliminates any interfacial incompatibilities, such as lack of adhesion,which may arise from using two different polymeric layers.

Polymers that can be used for a barrier layer include the examples ofpolymers listed above for the reservoir layer. Representative examplesof polymers for the barrier layer also include polytetrafluoroethylene,perfluoro elastomers, ethylene-tetrafluoroethylene copolymer,fluoroethylene-alkyl vinyl ether copolymer, polyhexafluoropropylene, lowdensity linear polyethylenes having high molecular weights,ethylene-olefin copolymers, atactic polypropylene, polyisobutene,polybutylenes, polybutenes, styrene-ethylene-styrene block copolymers,styrene-butylene-styrene block copolymers, styrene-isobutylene-styreneblock copolymers styrene-butadiene-styrene block copolymers, andethylene methacrylic acid copolymers of low methacrylic acid content.

EVAL is functionally a very suitable choice of polymer for the barrierlayer. The copolymer can comprise a mole percent of ethylene of fromabout 27% to about 48%. Fluoropolymers are also a suitable choice forthe barrier layer composition. For example, polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.) can be dissolved in acetone, methylethylketone,dimethylacetamide, and cyclohexanone, and can optionally be combinedwith EVAL to form the barrier layer composition. Also, solutionprocessing of fluoropolymers is possible, particularly the lowcrystallinity varieties such as CYTOP available from Asahi Glass andTEFLON AF available from DuPont. Solutions of up to about 15% (w/w) arepossible in perfluoro solvents, such as FC-75 (available from 3M underthe brand name FLUORINERT), which are non-polar, low boiling solvents.Such volatility allows the solvent to be easily and quickly evaporatedfollowing the application of the polymer-solvent solution to theimplantable device.

PBMA and ethylene-vinyl acetate copolymers can also be especiallysuitable polymers for the barrier layer. PBMA, for example, can bedissolved in a solution of xylene, acetone and HFE FLUX REMOVER(Techspray, Amarillo, Tex.). In another embodiment, the polymer in thebarrier layer is PBMA or a mixture of PBMA and an ethylene-vinyl acetatecopolymer.

Other choices of polymers for the rate-limiting membrane include, butare not limited to, ethylene-anhydride copolymers; and ethylene-acrylicacid copolymers having, for example, a mole % of acrylic acid of fromabout 2% to about 25%. The ethylene-anhydride copolymer available fromBynel adheres well to EVAL and thus would function well as a barrierlayer over a reservoir layer made from EVAL. The copolymer can bedissolved in organic solvents, such as dimethylsulfoxide anddimethylacetamide. Ethylene vinyl acetate polymers can be dissolved inorganic solvents, such as toluene and n-butyl acetate. Ethylene-acrylicacid copolymers can be dissolved in organic solvents, such as methanol,isopropyl alcohol, and dimethylsulfoxide.

Yet another choice of polymer for the rate-limiting membrane is across-linked silicone elastomer. Loose silicone and silicone with verylow cross-linking are thought to cause an inflammatory biologicalresponse. However, it is believed that a thoroughly cross-linkedsilicone elastomer, having low levels of leachable silicone polymer andoligomer, is an essentially non-inflammatory substance. Siliconeelastomers, such as Nusil MED-4750, MED-4755, or MED2-6640, having hightensile strengths, for example between 1200 psi and 1500 psi, willlikely have the best durability during crimping, delivery, and expansionof a stent as well as good adhesion to a reservoir layer, e.g., EVAL orthe surface of an implantable device.

The composition for a rate-reducing membrane or diffusion barrier layercan be prepared by the methods used to prepare a polymer solution asdescribed above. The polymer can comprise from about 0.1% to about 35%,more narrowly from about 1% to about 20% by weight of the total weightof the composition, and the solvent can comprise from about 65% to about99.9%, more narrowly from about 80% to about 98% by weight of the totalweight of the composition. Selection of a specific weight ratio of thepolymer and solvent depends on factors such as, but not limited to, thetype of polymer and solvent employed, the type of underlying reservoirlayer, and the method of application.

Forming a Primer Layer

The presence of an active agent in a polymeric matrix can interfere withthe ability of the matrix to adhere effectively to the surface of thedevice. Increasing the quantity of the active agent reduces theeffectiveness of the adhesion. High drug loadings in the coating canhinder the retention of the coating on the surface of the device. Aprimer layer can serve as a functionally useful intermediary layerbetween the surface of the device and an active agent-containing orreservoir coating. The primer layer provides an adhesive tie between thereservoir coating and the device—which, in effect, would also allow forthe quantity of the active agent in the reservoir coating to beincreased without compromising the ability of the reservoir coating tobe effectively contained on the device during delivery and, ifapplicable, expansion of the device.

The primer composition can be prepared by adding a predetermined amountof a polymer to a predetermined amount of a compatible solvent. By wayof example, and not limitation, the polymer can comprise from about 0.1%to about 35%, more narrowly from about 1% to about 20% by weight of thetotal weight of the composition, and the solvent can comprise from about65% to about 99.9%, more narrowly from about 80% to about 98% by weightof the total weight of the primer composition. A specific weight ratiois dependent on factors such as the molecular weight of the polymer, thematerial from which the implantable device is made, the geometricalstructure of the device, the choice of polymer-solvent combination, andthe method of application.

Representative examples of polymers for the primer layer include, butare not limited to, polyisocyanates, such as triisocyanurate andpolyisocyanate; polyethers; polyurethanes based on diphenylmethanediisocyanate; acrylates, such as copolymers of ethyl acrylate andmethacrylic acid; titanates, such as tetra-iso-propyl titanate andtetra-n-butyl titanate; zirconates, such as n-propyl zirconate andn-butyl zirconate; silane coupling agents, such as3-aminopropyltriethoxysilane and (3-glydidoxypropyl)methyldiethoxysilane; high amine content polymers, such aspolyethyleneamine, polyallylamine, and polylysine; polymers with a highcontent of hydrogen bonding groups, such as polyethylene-co-polyvinylalcohol, ethylene vinyl acetate, and melamine formaldehydes; andunsaturated polymers and prepolymers, such as polycaprolactonediacrylates, polyacrylates with at least two acrylate groups, andpolyacrylated polyurethanes. Poly methacrylate, such as polybutylmethacrylate and poly methyl methacrylate. Acrylate polymer such asethyl acrylate, and methyl acrylate and copolymer of acrylate andmethalcrylate. With the use of unsaturated prepolymers, a free radicalor UV initiator can be added to the composition for the thermal or UVcuring or cross-linking process, as is understood by one of ordinaryskill in the art.

Representative examples of polymers that can be used for the primermaterial also include those polymers that can be used for the reservoirlayer as described above. The use of the same polymer significantlyreduces or eliminates any interfacial incompatibilities, such as lack ofan adhesive tie or bond, which may exist with the employment of twodifferent polymeric layers.

EVAL is a very suitable choice of polymer for the primer layer. Thecopolymer possesses good adhesive qualities to the surface of a stent,particularly stainless steel surfaces, and has illustrated the abilityto expand with a stent without any significant detachment of thecopolymer from the stent surface. The copolymer can comprise a molepercent of ethylene of from about 27% to about 48%.

Methods for Applying the Compositions to the Device

Application of the composition can be by any conventional method, suchas by spraying the composition onto the prosthesis or by immersing theprosthesis in the composition. Operations such as wiping,centrifugation, blowing, or other web-clearing acts can also beperformed to achieve a more uniform coating. Briefly, wiping refers tophysical removal of excess coating from the stent surface;centrifugation refers to rapid rotation of the stent about an axis ofrotation; and blowing refers to application of air at a selectedpressure to the deposited coating. Any excess coating can also bevacuumed off the surface of the device.

Alternatively, primer can be deposited on the device through vapor phasepolymerization, such as parylene and parylene C. Primer can also formedthrough plasma polymer rization, such as polymerization of acrylicmonomer on the device surface directly.

If the optional primer layer is to be formed on the device, the primercomposition can first be applied to a designated region of the surfaceof the device. The solvent(s) is removed from the composition byallowing the solvent(s) to evaporate. The evaporation can be induced byroom temperature vacuum dry or heating the device at a predeterminedtemperature for a predetermined period of time. For example, the devicecan be heated at a temperature of about 50° C. for about 10 minutes toabout 24 hours. The heating can be conducted in an anhydrous atmosphereand at ambient pressure and should not exceed the temperature whichwould adversely affect the active agent. The heating can also beconducted under a vacuum condition.

The composition containing the active agent can be applied to adesignated region of the surface of the device. If the optional primerlayer has been formed on the surface of the device,active-agent-containing composition can be applied to the dry primerlayer. Thereafter, the solvent(s) can be removed from the reservoirlayer as described above for the primer layer.

Examples of the Device

Examples of implantable devices for the present invention includeself-expandable stents, balloon-expandable stents, stent-grafts, grafts(e.g., aortic grafts), artificial heart valves, cerebrospinal fluidshunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). Theunderlying structure of the device can be of virtually any design. Thedevice can be made of a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY), stainless steel (316L),high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloyL-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titaniumalloy, platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

In some embodiments, the device can be a bioabsorbable, biodegradable,or bioerodable stent having a drug in the body of the stent or in acoating on the stent.

The embodiments of the present invention may be particularly useful forcoating of small vessel stents. Small vessels stents can be generallycategorized as having inner diameters of less than 2.5 mm in an expandedstate. Because of their small size, small vessel stents offer uniquechallenges for drug delivery. In particular, as compared toconventionally sized stents, small vessel stents have a greater surfacearea to volume ratio. Therefore, when a small vessel stent is insertedinto a biological lumen, the vessel tissue surrounding a small vesselstent is exposed to a greater concentration of polymer. The presentinvention can be used to reduce the amount of polymer that is needed onthe stent structure and still maintain an effective release rate. Thepresent invention, therefore, can reduce the potential risk of aninflammatory response by the vessel tissue when small stents are used asa drug delivery device in small vessels.

Method of Use

In accordance with the above-described method, the active agent can beapplied to a device, e.g., a stent, retained on the device duringdelivery and released at a desired control rate and for a predeterminedduration of time at the site of implantation. A stent having theabove-described coating layers is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coatinglayers is particularly useful for treating occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents may be placedin a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, and coronaryarteries.

Briefly, an angiogram is first performed to determine the appropriatepositioning for stent therapy. Angiography is typically accomplished byinjecting a radiopaque contrasting agent through a catheter insertedinto an artery or vein as an x-ray is taken. A guidewire is thenadvanced through the lesion or proposed site of treatment. Over theguidewire is passed a delivery catheter, which allows a stent in itscollapsed configuration to be inserted into the passageway. The deliverycatheter is inserted either percutaneously, or by surgery, into thefemoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering the catheterthrough the vascular system under fluoroscopic guidance. A stent havingthe above-described coating layers may then be expanded at the desiredarea of treatment. A post insertion angiogram may also be utilized toconfirm appropriate positioning.

EXAMPLES

The embodiments of the invention will be illustrated by the followingset forth examples which are being given by way of illustration only andnot by way of limitation. All parameters and data are not be construedto unduly limit the scope of the embodiments of the invention.

Example 1

18 mm VISION stents (available from Guidant Corporation) were coated byspraying a 2% (w/w) solution of polybutylmethacrylate (“PBMA”) mixedwith a solvent blend of 60% acetone and 40% xylene (w/w). The solventwas removed by baking at 80° C. for 30 minutes. The target primer weightwas 160 μg. A to polymer ratio for the coating was 1.25 to 1, with atarget reservoir coating weight of 288 μg. The target drug loading was160 μg. The stents were then baked at 50° C. for 2 hours to produce drycoatings.

Example 2

The stents were separated into two test groups. Group A served as thecontrol group, and Group B was exposed to a fluid treatment. Inparticular, the stents of Group B were sprayed with a solution of pureethanol for five spray cycles. In particular, the following Table 4lists the spray process parameters that were used to conduct the fluidtreatment process: TABLE 4 Parameter Set Value Units Spray Head Spraynozzle temperature 26 ± 2  ° C. Atomization pressure (non-activated)  15± 2.5 psi Distance from spray nozzle to coating 10-12 mm mandrel pinSolution barrel pressure 2.5 psi Needle valve lift pressure 80 ± 10 psiHeat Nozzle Temperature 26 ± 2  ° C. Air Pressure 12-15 psi Distancefrom heat nozzle to coating 10-15 mm mandrel pin

The stents of Group B were then baked to essentially remove the ethanol.

Example 3

The drug-coated stents were placed on stent holders of a Vankel Bio-Disrelease rate tester (Vankel, Inc., Cary, N.C.). 3 stents from each testgroup were dipped into an artificial medium for about 1 hour to extractthe 40-O-(2-hydroxy)ethyl-rapamycin from the stent coatings. Theartificial medium included phosphate buffer saline solution (10 mM, pH7.4) and 1% TRITON X-100 Sigma Corporation) which stabilizes the40-O-(2-hydroxy)ethyl-rapamycin in the testing solution. Each stent wastested in a separate testing solution to prevent cross-contamination.After extraction, each of the solutions was separately analyzed for theamount of drug released from the stent coatings by high pressure liquidchromatography (HPLC). The HPLC system consisted of a Waters 2690system. After the drug solutions were analyzed by HPLC, the results werequantified by comparing the release rate results with a referencestandard.

Each of the stents was then dipped in fresh extraction solutions foranother 6 hours (7 hours total). The solutions were analyzed by HPLC asdescribed above. Finally, the stents were dipped in fresh extractionsolutions for another 17 hours (24 hours total). The solutions wereagain analyzed by HPLC as described above.

Next, the total drug content of the coatings was determined. First, 3stents from each test group were placed in volumetric flasks. Each stentwas placed in a separate flask. An appropriate amount of the extractionsolvent acetonitrile with 0.02% butylated hydroxytoluene as a protectantwas added to each flask. The flasks were sonicated for a sufficient timeto extract the entire drug from the reservoir regions. Then, thesolution in the flasks was filled to mark with the solvent solution, andthe drug solutions for each stent analyzed separately by HPLC. The HPLCrelease rate results were quantified by comparing the results with areference standard. The total drug content of the stents was thencalculated.

The drug release profile could then be generated by plotting cumulativedrug released in the medium vs. time. The percentage of drug released ata specific time was determined by comparing the cumulative drug releasedwith the total content data. The results demonstrate that the fluidtreatment process substantially reduces the active agent release rate.The results for the total content analysis are summarized in Table 5,the drug release profile is summarized in Table 6, and the release ratefor each test group is summarized in Table 7. TABLE 5 Group A Group BStent 1 Stent 2 Stent 3 Stent 1 Stent 2 Stent 3 Theoretical 149.4 174.4166.1 165.0 163.3 166.1 Total Recovery (μg) Total 142.4 161.6 150.7128.2 135.0 133.1 Recovered (μg) % Recovered 95 93 91 78 83 80

TABLE 6 Group A Group B (μg released) (μg released) Time (hours) Stent 1Stent 2 Stent 3 Stent 1 Stent 2 Stent 3  1 34.93 30.37 36.89 7.82 3.671.88  7 55.44 54.30 62.03 25.50 9.92 5.31 24 74.55 82.69 89.62 46.4016.84 10.14 Average for 82.29 24.46 Group (24 hours) Standard 7.54 19.29Deviation for Group

TABLE 7 Group A Group B (% of drug released) (% of drug released) Time(hours) Stent 1 Stent 2 Stent 3 Stent 1 Stent 2 Stent 3  1 25 19 24 5 21  7 39 34 41 17 7 4 24 52 51 59 31 11 7 Average for 54.35 16.24 Group(24 hours) Standard 4.49 12.80 Deviation for Group

Example 4

The following experiment was conducted in order to obtain information onhow the fluid treatment process could affect polymer pellet morphology.Pellets of poly(vinylidene fluoride-co-hexafluoropropylene) (SOLEF21508, available from Solvay Solexis PVDF, Thorofare, N.J.) were placedin a sealable container. The treatment fluid, ethyl acetate, was addedto the container at a 1:7 polymer:fluid ratio (w/w) and the containerwas sealed. The contents of the container were agitated at roomtemperature for about five hours by using a magnetic stir bar. Uponvisible inspection, the pellets about doubled in size, indicating thatthe fluid caused the polymer to swell. After the treatment, the polymerpellets were removed from the container and dried at 50° C. overnight.

A Fourier Transform Infrared (FTIR) analysis was conducted on a controlgroup (i.e., pellets of poly(vinylidene fluoride-co-hexafluoropropylene)which had not been exposed to the fluid treatment). The results for thecontrol group are illustrated in the spectrograph of FIG. 5A. An FTIRanalysis was also conducted on the pellets exposed to the fluidtreatment. The results for the fluid treatment group are illustrated inthe spectrograph of FIG. 5B. The spectra of FIGS. 5A and 5B aresubstantially similar, except that a peak near 975 cm⁻¹ appears for thepolymer treated with the fluid as shown in FIG. 5B.

It was confirmed by conducting a differential scanning calorimetry (DSC)experiment that the peak near 975 cm⁻¹ indicated an increase in percentcrystallinity for the polymer. In particular, it was determined that thepolymer treated with the fluid had a melting enthalpy of about 35J/gram, whereas a control sample of polymer that was untreated had amelting enthalpy of about 24 J/gram. The increased melting enthalpy ofthe treated polymer indicated an increase in percent crystallinity.

Example 5

18 mm VISION stents (available from Guidant Corporation) are coated byspraying a 2% (w/w) solution of poly(vinylidenefluoride-co-hexafluoropropylene) (e.g, SOLEF 21508) and40-O-(2-hydroxy)ethyl-rapamycin mixed with a solvent blend of 70:30acetone/cyclohexanone (w/w). The drug to polymer ratio for the coatingis 1.25 to 1. The target drug loading is 160 μg. The solvent is removedby baking at 50° C. for 2 hours to produce a dry drug coating. Next, thestents are immersed in a hydrofluoroether solvent (e.g., NOVEC HFE7200,ethoxy-nonafluorobutane (C₄F₉OC₂H₅), available from 3M, St. Paul, Minn.)for five minutes for a fluid treatment. The stents are then removed fromthe hydrofluoroether solvent and baked to remove essentially all of thefluid.

Example 6

18 mm VISION stents (available from Guidant Corporation) are coated byspraying a 2% (w/w) solution of PBMA mixed with a solvent blend of 60%acetone and 40% xylene (w/w). The solvent is removed by baking at 80° C.for 30 minutes. The target primer weight is 160 μg. A solution of 2%(w/w) PBMA and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 60%acetone and 40% xylene (w/w) is spray coated onto the stents. The drugto polymer ratio for the coating is 1.25 to 1, with a target reservoircoating weight of about 288 μg. The target drug loading is 160 μg. Thestents are then baked at 50° C. for 2 hours to produce dry coatings.Next, the stents are sprayed with acetone for five spray cycles. Theacetone is allowed to evaporate to remove essentially all of the fluidfrom the coatings.

Example 7

The data contained in Table 8 demonstrates a reduction in thevariability of an active agent's release rate when polylacticacid-coated stents are treated with acetone. Polylactic acid-coatedstents containing active agent were used for both the test group and thecontrol group. The test group was treated with acetone. The controlgroup was not treated with acetone. There were 12 samples tested for thetest group and 12 samples tested for the control group. Each stent wasmeasured at 2 hours, 6 hours, 24 hours, and 48 hours for the amount ofactive agent released using a standard release rate STM test. The meanand variance are standard statistical descriptions of a data set(mean=average of all data points; variance=(standard deviation)². TheF-value and F-critical are parameters calculated when performing atwo-sample F-Test for variance. The test was used to determine if thereis a statistical difference in the variance of two groups. There is astatistical difference in the variances of two groups when the F-valueis greater than the F-critical.

As illustrated, the data in Table 8 shows the reduction in release ratevariability of polylactic acid-coated stents that are exposed withacetone mist. A reduction in variability for the amount of active agentthat was released at time points of 2, 6, 24, and 48 hours was observed,with a statistically significant reduction of variability at 2 hours and48 hours when using an F-test with a significance level of 0.05. TABLE 8Time of release (hours) 2 6 24 48 Amount of active agent released for59.6 67.2 76.9 81.6 control stents (mean) Variance of control stents106.2 104.3 87.5 73.8 Amount of active agent released for 44.1 56.2 69.273.7 acetone-treated stent (mean) Variance of acetone-treated stents30.9 37.8 31.6 24 F-Value 3.44 2.76 2.77 3.08 F-Critical 2.82 2.82 2.822.82

As illustrated, the variance of the acetone-treated stents at 2, 6, 24,and 48 hours are lower than the variance of the control stents at 2, 6,24, and 48 hours. Therefore, the stents treated with acetone have areduction in release rate variability.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of manufacturing a drug delivery implantable medical device,comprising: 1) applying a composition to the device to form a wetcoating, the composition comprising a polymer, a first fluid, andoptionally an active agent; 2) applying a second fluid to the wetcoating, the second fluid being substantially or completely free fromany polymers; and 3) removing the first fluid and the second fluid toform a dry coating.
 2. The method of claim 1 wherein the second fluid isin a vapor phase.
 3. The method of claim 1 wherein the second fluid isin a liquid phase.
 4. The method of claim 1 wherein the first fluid andthe second fluid are the same.
 5. The method of claim 1 wherein thefirst fluid and the second fluid are different.
 6. The method of claim 1wherein the first fluid is a blend of two or more solvents.
 7. Themethod of claim 1 wherein the device is a stent.
 8. The method of claim1 wherein the polymer comprises a blend of two or more polymers.
 9. Themethod of claim 1 wherein the polymer comprises a copolymer.
 10. Themethod of claim 1 wherein the wet coating has a first fluid contentpercentage (w/w) selected from a group consisting of greater than 10%,great than 20%, greater than 30%, greater than 40%, and greater than50%.
 11. The method of claim 1 wherein the active agent at leastpartially dissolves when exposed to the second fluid.
 12. The method ofclaim 1 wherein the second fluid is a non-solvent for the active agent.13. The method of claim 1 wherein the second fluid does not cause theactive agent to precipitate.
 14. The method of claim 1 wherein thesecond fluid does not cause the active agent to cluster.
 15. The methodof claim 1 wherein the second fluid does not cause the active agent tocrystallize.
 16. The method of claim 1 wherein the second fluid does notcause the active agent to solidify.
 17. The method of claim 1 whereinthe second fluid is selected from the group consisting of chloroform,acetone, cyclohexanone, water, dimethylsulfoxide, propylene glycolmethyl ether, iso-propylalcohol, n-propylalcohol, iso-propanol,methanol, ethanol, tetrahydrofuran, dimethylformamide,dimethylacetamide, benzene, toluene, xylene, hexane, cyclohexane,pentane, heptane, octane, nonane, decane, decalin, ethyl acetate, butylacetate, isobutyl acetate, isopropyl acetate, butanol, diacetonealcohol, benzyl alcohol, 2-butanone, dioxane, methylene chloride, carbontetrachloride, ietrachloroethylene, tetrachloroethane, chlorobenzene,1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, acetonitrile, hexamethyl phosphoramide, and anymixtures thereof in any proportion.
 18. The method of claim 1 whereinthe second fluid is substantially or completely free from any activeagents.
 19. The method of claim 1 wherein the second fluid is a vaporthat includes a cycloether.
 20. The method of claim 1 wherein applyingthe second fluid to the wet coating comprises applying the fluid to adesignated portion of the wet coating such that at least some of the wetcoating does not get exposed to the second fluid.
 21. The method ofclaim 1 wherein applying the second fluid to the wet coating comprisesspraying the second fluid at a rate of about 0.1 mL/hr to about 50 mL/hrthrough an atomization spray nozzle with atomization gas pressuresranging from about 1 psi to about 30 psi.
 22. The method of claim 1wherein after applying the second fluid to the wet coating, the contentof the active agent in the coating is at least 80% of the content of theactive agent in the coating before applying the fluid.
 23. The method ofclaim 1 wherein after applying the second fluid to the wet coating, thecontent of the active agent in the coating is at least 90% of thecontent of the active agent in the coating before applying the fluid.24. The method of claim 1 wherein the duration of exposure of the secondfluid is sufficient to decrease the active agent release rate from thedry coating after the dry coating has been implanted into a biologicallumen.
 25. The method of claim 1 further comprising forming a primerlayer on a surface of the implantable medical device before applying thecomposition.
 26. The method of claim 1 wherein the wet coating does notinclude an active agent; is applied to a reservoir layer containing anactive agent; and forms a barrier layer over the reservoir layer. 27.The method of claim 1 wherein the second fluid is a volatile fluidhaving a boiling point below 60 deg. C. at atmospheric pressure.
 28. Themethod of claim 1 wherein the second fluid is a more effective solventfor the active agent than the second fluid is for the polymer.
 29. Themethod of claim 1 wherein the second fluid at least partially dissolvesin the active agent, but does not dissolve in the polymer.
 30. Themethod of claim 1 wherein the application of the second fluid causes thepercent crystallinity of the polymer to increase.
 31. The method ofclaim 1 wherein the second fluid is chilled.
 32. The method of claim 1wherein the temperature of the second fluid is below 25 deg C.
 33. Themethod of claim 1 wherein the temperature of the second fluid is equalto or greater than the glass transition temperature of the polymer. 34.The method of claim 1 wherein the temperature of the second fluid isbelow the melting temperature of the polymer.
 35. The method of claim 1wherein the temperature of the second fluid is equal to or greater thanthe glass transition temperature of the polymer and below the meltingtemperature of the polymer.
 36. The method of claim 1 wherein thetemperature of the second fluid is at or about the crystallizationtemperature of the polymer.